Sphingolipidoses are characterized by the pathological accumulation of a specific sphingolipid in various organs and tissues, which is known to be due to the deficiency of a specific lysosomal hydrolase. This proposed study will use the cellular uptake process of exogenous sphingolipids to focus on the lysosomal degradation of sphingolipidoses in the sphingolipidoses fibroblast to investigate the relationship of sphingolipids accumulation and their lysosomal hydrolases in hoping to learn the mechanism of sphingolipid storage in human fibroblasts. Alternatively, we also plan to study the de novo synthesis of sphingolipids and their degradation. Since an abnormally lower density of lysosomal fraction in Farber's fibroblasts than that of control cells was found in our preliminary study, it may enable us to isolate a series of lysosomal fractions from some sphingolipidoses fibroblasts to investigate the biochemical and morphological abnormalities of lysosomes in sphingolipidoses fibroblasts. We propose to study the sequentially degradative processes of sphingolipids in intact sphingolipidoses fibroblasts as well as the lysosomal fructose isolated from these cells to assess the effect of accumulation of sphingolipids on the catabolic processes of sphingolipids in lysosomes. A systematic investigation of lysosomal degradation of sphingolipids in both sphingolipidoses and normal fibroblasts may help us to learn what precise mechanism causes the diverse clinical manifestation and how the known enzyme deficiencies cause the tissue damage in sphingolipidoses.